HIV infection causes significant morbidity and mortality worldwide. Highly active antiretroviral therapy has dramatically reduced the risk of AIDS, opportunistic illnesses and mortality directly related to immune suppression. However, with the increased longevity of HIV infected persons, it is now evident that they are at increased risk of developing a variety of non-AIDS conditions including cardiovascular, renal, endocrine and neurologic diseases. A growing body of evidence implicates chronic inflammation and immune activation in the development of these non-AIDS conditions. We have shown that inflammasome activation as measured by interleukin-18 (IL-18) production occurs during both HIV and other chronic viral infections. Plasma from infected subjects as well as purified virus preparations stimulate monocytes to produce IL-18. We hypothesize that such viruses induce chronic low-level immune activation by sustaining abnormal inflammasome activity in monocyte lineage cells. This proposal addresses the mechanism by which RNA viruses capable of establishing chronic infections stimulate the inflammasome complex in monocytes regardless of whether they directly infect these cells. We will (1) determine whether Toll-like receptors, which have been previously shown to activate inflammasomes during bacterial infection, also recognize and activate inflammasomes during viral infections. (2) We will examine how the extracellular cytokine environment alters inflammasome activity and; (3) study the role of virus uptake by endocytosis in inflammasome activation. This work will enhance our understanding of immune activation caused by these important viruses. A clear understanding of this process will have implications for managing and treating both the primary viral infection and the co-morbid medical conditions, which are often exacerbated by prolonged immune activation.